tbuckley/cabot-search huggingface dataset:
Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer
Authors: Vincenzo Nasca, Francesco Barretta, Francesca Corti, Sara Lonardi, Monica Niger, Maria Elena Elez, Marwan Fakih, Priya Jayachandran, Aakash Tushar Shah, Massimiliano Salati, Elisabetta Fenocchio, Lisa Salvatore, Chiara Cremolini, Javier Ros, Margherita Ambrosini, Giacomo Mazzoli, Rossana Intini, Michael J Overman, Rosalba Miceli, Filippo Pietrantonio
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.
Interdependent Nuclear Co-Trafficking of ASPP1 and p53 Aggravates Cardiac Ischemia/Reperfusion Injury
Authors: Ying Yang, Yang Zhang, Jiqin Yang, Manman Zhang, Tao Tian, Yuan Jiang, Xuening Liu, Genlong Xue, Xingda Li, Xiaofang Zhang, Shangxuan Li, Xiang Huang, Zheng Li, Yang Guo, Lexin Zhao, Hairong Bao, Zhiwen Zhou, Jiahui Song, Guohui Yang, Lina Xuan, Hongli Shan, Zhiren Zhang, Yanjie Lu, Baofeng Yang, Zhenwei Pan
Journal: Circulation Research (2022)

ASPP1 (apoptosis stimulating of p53 protein 1) is critical in regulating cell apoptosis as a cofactor of p53 to promote its transcriptional activity in the nucleus. However, whether cytoplasmic ASPP1 affects p53 nuclear trafficking and its role in cardiac diseases remains unknown. This study aims to explore the mechanism by which ASPP1 modulates p53 nuclear trafficking and the subsequent contribution to cardiac ischemia/reperfusion (I/R) injury.The immunofluorescent staining showed that under normal condition ASPP1 and p53 colocalized in the cytoplasm of neonatal mouse ventricular cardiomyocytes, while they were both upregulated and translocated to the nuclei upon hypoxia/reoxygenation treatment. The nuclear translocation of ASPP1 and p53 was interdependent, as knockdown of either ASPP1 or p53 attenuated nuclear translocation of the other one. Inhibition of importin-β1 resulted in the cytoplasmic sequestration of both p53 and ASPP1 in neonatal mouse ventricular cardiomyocytes with hypoxia/reoxygenation stimulation. Overexpression of ASPP1 potentiated, whereas knockdown of ASPP1 inhibited the expression of Bax (Bcl2-associated X), PUMA (p53 upregulated modulator of apoptosis), and Noxa, direct apoptosis-associated targets of p53. ASPP1 was also increased in the I/R myocardium. Cardiomyocyte-specific transgenic overexpression of ASPP1 aggravated I/R injury as indicated by increased infarct size and impaired cardiac function. Conversely, knockout of ASPP1 mitigated cardiac I/R injury. The same qualitative data were observed in neonatal mouse ventricular cardiomyocytes exposed to hypoxia/reoxygenation injury. Furthermore, inhibition of p53 significantly blunted the proapoptotic activity and detrimental effects of ASPP1 both in vitro and in vivo.Binding of ASPP1 to p53 triggers their nuclear cotranslocation via importin-β1 that eventually exacerbates cardiac I/R injury. The findings imply that interfering the expression of ASPP1 or the interaction between ASPP1 and p53 to block their nuclear trafficking represents an important therapeutic strategy for cardiac I/R injury.
Advisory Board and Contents
Authors: Yang Zheng, Hao Li, Xiaochen Bo, Hebing Chen, Alice Godden, Simone Immler, Gabriel Dupré, Romain Volmer, Vinodh Sahayasheela, Zutao Yu, Takuya Hidaka, Ganesh Pandian, Hiroshi Sugiyama, Jingni Wu, Wei Hu, Shengli Li
Journal: Trends in Genetics (2022)
Outcomes of Percutaneous Intervention in Patients With Takayasu Arteritis
Authors: George Joseph, Viji S. Thomson, Thomas V. Attumalil, Pratheesh G. Mathen, Arpudh M. Anandaraj, Oommen K. George, Paul V. George, Ruchika Goel, Sathish Kumar, John Mathew, Debashish Danda
Journal: Journal of the American College of Cardiology (2023)

The status of vascular lesion treatment using percutaneous intervention (PI) in Takayasu arteritis (TAK) remains unresolved. This study sought to develop PI strategies appropriate for TAK. A prospectively maintained single-center database of TAK PI procedures from 1996 to 2022 was analyzed retrospectively. Obstructive lesions were treated by elective stenting (using bare or covered stents), balloon angioplasty (BA), or cutting-balloon angioplasty (CBA), with adjunctive stenting for suboptimal BA or CBA results. PIs were repeated in restenotic lesions until sustained success was obtained. Aortic or peripheral aneurysms and spontaneous aortic dissections were treated with covered stents or endografts. Immunosuppressive therapy, started before PI, was continued long term. A total of 942 patients underwent PI to treat 2,450 arterial lesions (2,365 stenoses or occlusions, 85 aneurysms or dissections) in 630 subclavian or axillary, 586 renal, 463 aortic, 333 carotid, 188 mesenteric, 116 iliac, 71 coronary, and 63 other arteries; 3,805 PIs were performed (1.55 PIs per lesion; range 1-7 PIs per lesion). Early success was obtained in 2,262 (92.3%), and late success in 1,460 (84.5%) of 1,727 lesions with a median of 39 months (IQR: 15-85 months) of follow-up. Repeated PIs increased late success in obstructive lesions from 48.6% to 83.3%. A total of 1,687 elective stenting lesions achieved 88% late success with 1.49 PIs per lesion; covered stents (1.18 PIs per lesion) restenosed less than bare stents (1.51 PIs per lesion; P < 0.001). A total of 183 (36%) of 513 BA-treated lesions had good outcomes without adjunctive stenting; 122 CBA-treated lesions had 19% dissections and 8% ruptures or pseudoaneurysm formations. Aneurysms or dissections had 91.3% late success after PI. A total of 472 complications occurred in 415 (17%) lesions; 375 (79%) were resolved. Most vascular lesions in TAK can be effectively, safely, and durably treated using predominantly stent-based PI strategies.
Infections and Cardiovascular Disease
Authors: Juan M. Farina, Kiera Liblik, Pablo Iomini, Andrés F. Miranda-Arboleda, Clara Saldarriaga, Ivan Mendoza, Ezequiel J. Zaidel, José M. Rubio-Campal, Alvaro Sosa-Liprandi, Adrian Baranchuk
Journal: Journal of the American College of Cardiology (2023)
Audio Summary
Journal: Journal of the American College of Cardiology (2023)

This JACC Focus Seminar provides an overview of and highlights recently published research on cardiomyopathies and nutritional heart disease that have a higher prevalence in tropical regions. The development of tropical cardiomyopathies and nutritional cardiovascular disease (CVD) is complicated by high rates of poverty, fragmented health care systems, and suboptimal access to health care because of socioeconomic inequalities, leading to the fact that children, adolescents, and young adults are disproportionally affected. Such tropical cardiomyopathies and nutritional CVD that have not been prevalent in high-income countries in the past decades are now reemerging. When treating migrants or refugees, it is important for attending physicians to consider the burden of endemic diseases in the countries of origin and the likelihood that such patients might be affected. In this review, the authors propose an approach for adequate diagnostic work-up leading to appropriate care for those with suspected or confirmed tropical cardiomyopathies and nutritional CVD.
Heart Failure Readmissions
Authors: Prihatha R. Narasimmaraj, Rishi K. Wadhera
Journal: JACC Heart Failure (2023)

High out-of-pocket prescription drug costs contribute to financial toxicity, medication nonadherence, and adverse cardiovascular (CV) outcomes. Policymakers recently passed the Inflation Reduction Act, which will cap Medicare out-of-pocket drug costs at $2,000/year and expand full low-income subsidies (LIS). It is unclear how these provisions will affect Medicare beneficiaries with CV risk factors and/or conditions.The authors sought to characterize the population of Medicare beneficiaries with CV risk factors/conditions experiencing out-of-pocket prescription drug costs >$2,000/year and estimate their potential savings under the Inflation Reduction Act's spending cap; identify sociodemographic characteristics associated with out-of-pocket costs >$2,000/year; and characterize beneficiaries newly eligible for LIS under the Inflation Reduction Act.This was a cross-sectional study of Medicare beneficiaries aged ≥65 years with ≥1 CV risk factor/condition from 2016 to 2019.An annual estimated 34,056,335 ± 855,653 Medicare beneficiaries (mean ± SE) had ≥1 CV risk factor/condition, of whom 1,020,484 ± 77,055 experienced out-of-pocket drug costs >$2,000/year. The likelihood of experiencing out-of-pocket drug costs >$2,000/year was lower among adults ≥75 years vs 65 to 74 years (adjusted OR: 0.67; 95% CI: 0.49-0.93) and for low-income vs higher-income adults. Among beneficiaries currently spending >$2,000/year, estimated median out-of-pocket drug savings would be $855/year and total annual savings $1,723,031,307 ± $91,150,609 under the Inflation Reduction Act. An estimated 1,289,861 beneficiaries would also become newly eligible for LIS.More than 1 million older adults with CV risk factors and/or conditions spend >$2,000/year out-of-pocket on prescription drugs and will likely benefit from the Inflation Reduction Act's cap, with estimated total out-of-pocket savings of $1.7 billion/year, while another 1.3 million will also become newly eligible for LIS.
Monocyte-neutrophil entanglement in glioblastoma
Authors: Dinorah Friedmann-Morvinski, Dolores Hambardzumyan
Journal: Journal of Clinical Investigation (2023)

Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.
The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic
Authors: Fergus Stafford, Neesha Krishnan, Ebony Richardson, Alexandra Butters, Sophie Hespe, Charlotte Burns, Belinda Gray, Caroline Medi, Natalie Nowak, Julia C. Isbister, Hariharan Raju, David Richmond, Mark P. Ryan, Emma S. Singer, Raymond W. Sy, Laura Yeates, Richard D. Bagnall, Christopher Semsarian, Jodie Ingles
Journal: Genome Medicine (2022)

The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease.
Differential response to prolonged amoxicillin treatment: long-term resilience of the microbiome versus long-lasting perturbations in the gut resistome
Authors: Achal Dhariwal, Lars Christian Haugli Bråten, Kjersti Sturød, Gabriela Salvadori, Ahmed Bargheet, Heidi Åmdal, Roger Junges, Dag Berild, John-Anker Zwart, Kjersti Storheim, Fernanda Cristina Petersen
Journal: Gut Microbes (2022)

The collateral impact of antibiotics on the microbiome has attained increasing attention. However, the ecological consequences of long-term antibiotic exposure on the gut microbiome, including antibiotic resistance, are still limited. Here, we investigated long-term exposure effects to amoxicillin on the human gut microbiome and resistome. Fecal samples were collected from 20 patients receiving 3-months of amoxicillin or placebo treatment as part of a Norwegian multicenter clinical trial on chronic low back pain (AIM study). Samples were collected at baseline, last day of treatment, and 9 months after antibiotic cessation. The abundance and diversity of microbial and resistome composition were characterized using whole shotgun and functional metagenomic sequencing data. While the microbiome profiles of placebo subjects were stable over time, discernible changes in diversity and overall microbiome composition were observed after amoxicillin treatment. In particular, health-associated short-chain fatty acid producing species significantly decreased in proportion. However, these changes were short-lived as the microbiome showed overall recovery 9 months post-treatment. On the other hand, exposure to long-term amoxicillin was associated with an increase in total antimicrobial resistance gene load and diversity of antimicrobial resistance genes, with persistent changes even at 9 months post-treatment. Additionally, beta-lactam resistance was the most affected antibiotic class, suggesting a targeted response to amoxicillin, although changes at the gene level varied across individuals. Overall, our results suggest that the impact of prolonged amoxicillin exposure was more explicit and long-lasting in the fecal resistome than in microbiome composition. Such information is relevant for designing rational administration guidelines for antibiotic therapies.
Case 40-2022: A 38-Year-Old Man with Exertional Chest Discomfort
Authors: J. Sawalla Guseh, Anushri Parakh, Yen-Lin E. Chen, Thoralf M. Sundt, Michael G. Fitzsimons, Nikolaos Stathatos, Cynthia Harris
Journal: New England Journal of Medicine (2022)

A 38-year-old man with no cardiac risk factors was evaluated because of episodic chest discomfort occurring over several months, which was worse with exertion and better with rest. Management decisions were made.
Haloperidol for Treatment of ICU Delirium — Progress or Setback?
Authors: Edward R. Marcantonio
Journal: New England Journal of Medicine (2022)

Delirium is common, morbid, and costly in hospitalized older adults and in adults of all ages in the intensive care unit (ICU).1 Multifactorial nonpharmacologic interventions can prevent delirium, but there are no approved treatments.1,2 In 2018, the investigators of the large Modifying the Impact of ICU-Associated Neurological Dysfunction–USA (MIND-USA) trial concluded that antipsychotic agents were not effective for treatment of delirium,3 and in 2019, two systematic reviews commissioned by the Agency for Healthcare Research and Quality concluded that antipsychotics were not effective for treatment or prevention.4,5 However, these studies did not rule out targeted use of antipsychotics for behaviors that . . .
Melanin nanoparticles alleviate sepsis-induced myocardial injury by suppressing ferroptosis and inflammation
Authors: Chang Liu, Quan Zou, Huixin Tang, Jia Liu, Shiqi Zhang, Caihong Fan, Junwei Zhang, Ruiqing Liu, Yashan Liu, Ruiyan Liu, Yan Zhao, Qiang Wu, Zhi Qi, Yanna Shen
Journal: Bioactive Materials (2022)

Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro, MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.
Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging, drug targeting and delivery
Authors: Jing Chen, Peng Ji, Giri Gnawali, Mengyang Chang, Feng Gao, Hang Xu, Wei Wang
Journal: Acta Pharmaceutica Sinica B (2022)

The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as "overexpressed" biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug, which ultimately leads to effective and safe cancer therapy.
Time to negative PCR conversion amongst high-risk patients with mild-to-moderate Omicron BA.1 and BA.2 COVID-19 treated with sotrovimab or nirmatrelvir
Authors: Guillaume Martin-Blondel, Anne-Geneviève Marcelin, Cathia Soulié, Sofia Kaisaridi, Clovis Lusivika-Nzinga, Karen Zafilaza, Céline Dorival, Laura Nailler, Anaïs Boston, Anne-Marie Ronchetti, Cléa Melenotte, André Cabié, Christophe Choquet, Albert Trinh-Duc, Karine Lacombe, Géraldine Gaube, François Coustillères, Valérie Pourcher, Jean-Philippe Martellosio, Nathan Peiffer-Smadja, Marie Chauveau, Pierre Housset, Lionel Piroth, Mathilde Devaux, Gilles Pialoux, Aurélie Martin, Vincent Dubee, Jérôme Frey, Audrey Le Bot, Charles Cazanave, Philippe Petua, Roland Liblau, Fabrice Carrat, Youri Yordanov
Journal: Clinical Microbiology and Infection (2022)
Table of Contents
Authors: A Salawu, I Tannock, L Atwoli, G Erhabor, A Gbakima, A Haileamlak, J.-M Kayembe Ntumba, J Kigera, L Laybourn-Langton, B Mash, J Muhia, F Mulaudzi, D Ofori-Adjei, F Okonofua, A Rashidian, M El-Adawy, S Sidibé, A Snouber, J Tumwine, P Yassien, L Yonga, C Zakhama, A Cervantes, R Adam, S Roselló, D Arnold, N Normanno, J Taïeb, J Seligmann, T De Baere, P Osterlund, T Yoshino, E Martinelli, C Sessa, J Balmaña, S Bober, M Cardoso, N Colombo, G Curigliano, S Domchek, D Evans, D Fischerova, N Harbeck, C Kuhl, B Lemley, E Levy-Lahad, M Lambertini, J Ledermann, S Loibl, K.-A Phillips, S Paluch-Shimon, M Mirza, X Wu, J Zhu, R Yin, J Yang, J Liu, J Wang, L Wu, Z Liu, Y Gao, D Wang, G Lou, H Yang, Q Zhou
Journal: Annals of Oncology (2022)
Determinants of approved acetylcholinesterase inhibitor response outcomes in Alzheimer’s disease: relevance for precision medicine in neurodegenerative diseases
Authors: Simone Lista, Andrea Vergallo, Stefan J. Teipel, Pablo Lemercier, Filippo Sean Giorgi, Audrey Gabelle, Francesco Garaci, Nicola B. Mercuri, Claudio Babiloni, Bhakta Prasad Gaire, Yosef Koronyo, Maya Koronyo-Hamaoui, Harald Hampel, Robert Nisticò
Journal: Ageing Research Reviews (2022)
Assessing Cost-effectiveness From the LOGICA Trial—Is Laparoscopic Gastrectomy Worth the Cost?
Authors: Caitlin A. McIntyre, Harrison M. Drebin, Vivian E. Strong
Journal: JAMA Surgery (2022)

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Clinical Connections
Journal: Arthritis & Rheumatology (2022)

Gut dysbiosis in SpA is proportional to disease activity.• It is characterized by a reduction of bacterial diversity, a decreased abundance of Clostridiales, and an increased abundance of few potentially pathogenic species, including R gnavus.• In healthy siblings of SpA patients, HLA-B27 is associated with dysbiosis that may reflect subclinical gut inflammation and pave the way to full-blown SpA.